Ocular Gene Therapy in a Patient with Dystrophic Epidermolysis Bullosa.

Dystrophic epidermolysis bullosa is a rare genetic disease caused by damaging variants in COL7A1, which encodes type VII collagen. Blistering and scarring of the ocular surface develop, potentially leading to blindness. Beremagene geperpavec (B-VEC) is a replication-deficient herpes simplex virus type 1-based gene therapy engineered to deliver functional human type VII collagen. Here, we report the case of a patient with cicatrizing conjunctivitis in both eyes caused by dystrophic epidermolysis bullosa who received ophthalmic administration of B-VEC, which was associated with improved visual acuity after surgery.

Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation.

BACKGROUND: Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited. METHODS: We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA2DS2VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis. RESULTS: Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted. CONCLUSIONS: Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).

The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder.

Despite potent suppression of HIV-1 viral replication in the central nervous system (CNS) by antiretroviral therapy (ART), between 15% and 60% of HIV-1-infected patients receiving ART exhibit neuroinflammation and symptoms of HIV-1-associated neurocognitive disorder (HAND) - a significant unmet challenge. We propose that the emergence of HIV-1 from latency in microglia underlies both neuroinflammation in the CNS and the progression of HAND. Recent molecular studies of cellular silencing mechanisms of HIV-1 in microglia show that HIV-1 latency can be reversed both by proinflammatory cytokines and by signals from damaged neurons, potentially creating intermittent cycles of HIV-1 reactivation and silencing in the brain. We posit that anti-inflammatory agents that also block HIV-1 reactivation, such as nuclear receptor agonists, might provide new putative therapeutic avenues for the treatment of HAND.

Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents.

BACKGROUND: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority. METHODS: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations. RESULTS: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1st- (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05). CONCLUSION: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents.

Synthesis and evaluation of nanosized aluminum MOF encapsulating Umbelliferon: assessing antioxidant, anti-inflammatory, and wound healing potential in an earthworm model.

Nanoporous aluminum metal-organic framework (Al-MOF) was synthesized via solvothermal methods and employed as a carrier matrix for in vitro drug delivery of Umbelliferon (Um). The encapsulated Um was gradually released over seven days at 37 °C, using simulated body fluid phosphate-buffered saline (PBS) at pH 7.4 as the release medium. The drug release profile suggests the potential of Al-MOF nanoparticles as effective drug delivery carriers. Structural and chemical analyses of Um-loaded Al-MOF nanoparticles (Um-Al MOF) were conducted using Fourier-transform infrared (FTIR) spectroscopy, X-ray diffractometry (XRD), and ultraviolet-visible (UV-Vis) spectroscopy. Thermal gravimetric analysis (TGA) was employed to investigate the thermal stability of the Al-MOF nanoparticles, while Transmission Electron Microscopy (TEM) was utilized to assess their morphological features. Um-Al MOF nanoparticles demonstrated notable antioxidant and anti-inflammatory properties compared to Um and Al-MOF nanoparticles individually. Moreover, they exhibited significant enhancement in wound healing in an earthworm model. These findings underscore the potential of Al-MOF nanoparticles as a promising drug delivery system, necessitating further investigations to explore their clinical applicability.

Digital Health: From Remote Monitoring to Remote Care.

The growth of digital health technology has led to innovative technological solutions that can help to improve patient care. However, the primary focus to date has been on the passive monitoring of patients, which poses difficulties in clinical integration and has not succeeded in optimizing care for chronic conditions. In this article, we highlight the move from a digital care model focused on the passive monitoring of medical conditions to one where holistic patient management is provided by dedicated external health care teams on a longitudinal basis. This underlines the shift from remote patient monitoring to remote patient care. This approach has thus far mostly been applied at small scales, limited to specific institutions and environments. Generalization to the wider population will likely require the use of centralized entities that can scale these approaches. It is crucial to note that the role of this technology will be to supplement, rather than supplant, in-person care by allowing physicians to focus on the most relevant clinical data collected on a longitudinal basis. This approach is particularly promising for individuals living in rural or underserved areas, where traditional models of care may face barriers in implementation.

A systematic review and meta-analysis of the efficacy and safety of Mavacamten therapy in international cohort of 524 patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common heritable myocardial disorder worldwide. Current pharmacological treatment options are limited. Mavacamten, a first-in-class cardiac myosin inhibitor, targets the main underlying pathology of HCM. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Mavacamten in patients with HCM. PRISMA flow chart was utilized using PubMed, SCOPUS, and Cochrane databases for all up-to-date studies using pre-defined keywords. Pre-specified efficacy outcomes comprised several parameters, including an improvement in peak oxygen consumption (pVO2) and ≥ 1 NYHA class, the need for septal reduction therapy (SRT), change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ), changes in biochemical markers and LVEF, along with peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Safety outcomes included morbidity and serious adverse events. This systematic review included five studies, four RCTs and one non-randomized control trial comprised a total of 524 (Mavacamten [273, 54.3%] vs placebo [230, 45.7%] adult (≥ 18 years) patients with a mean age of 56 years. The study. comprised patients with Caucasian and Chinese ethnicity and patients with obstructive (oHCM) and non-obstructive (nHCM) HCM. Most baseline characteristics were similar between the treatment and placebo groups. Mavacamten showed a statistically significant increase in the frequency of the primary composite endpoint (RR = 1.92, 95% CI [1.28, 2.88]), ≥ 1 NYHA class improvement (RR = 2.10, 95% CI [1.66, 2.67]), a significant decrease in LVEF, peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Mavacamten also showed a significant reduction in SRT rates (RR = 0.29, 95% CI [0.21, 0.40], p < 0.00001), KCCQ clinical summary scores (MD = 8.08, 95% CI [4.80, 11.37], P < 0.00001) troponin levels and N-terminal pro-B-type natriuretic peptide levels. However, there was no statistically significant difference between Mavacamten and placebo regarding the change from baseline peak oxygen consumption. Mavacamten use resulted in a small increase in adverse events but no statistically significant increment in serious adverse events. Our study showed that Mavacamten is a safe and effective treatment option for Caucasian and Chinese patients with HCM on the short-term. Further research is needed to explore the long-term safety and efficacy of Mavacamten with HCM. In addition, adequately powered studies including patients with nHCM is needed to ascertain befits of Mavacamten in those patients.

A novel functionalized CuTi hybrid nanocomposites: facile one-pot mycosynthesis, characterization, antimicrobial, antibiofilm, antifouling and wastewater disinfection performance.

BACKGROUND: The continuous progress in nanotechnology is rapid and extensive with overwhelming futuristic aspects. Through modernizing inventive synthesis protocols, a paradigm leapfrogging in novelties and findings are channeled toward fostering human health and sustaining the surrounding environment. Owing to the overpricing and jeopardy of physicochemical synthesizing approaches, the quest for ecologically adequate schemes is incontestable. By developing environmentally friendly strategies, mycosynthesis of nanocomposites has been alluring. RESULTS: Herein, a novel architecture of binary CuO and TiO2 in nanocomposites form was fabricated using bionanofactory Candida sp., for the first time. For accentuating the structural properties of CuTi nanocomposites (CuTiNCs), various characterization techniques were employed. UV-Vis spectroscopy detected SPR at 350 nm, and XRD ascertained the crystalline nature of a hybrid system. However, absorption peaks at 8, 4.5, and 0.5 keV confirmed the presence of Cu, Ti and oxygen, respectively, in an undefined assemblage of polygonal-spheres of 15-75 nm aggregated in the fungal matrix of biomolecules as revealed by EDX, SEM and TEM. However, FTIR, ζ-potential and TGA reflected long-term stability (- 27.7 mV) of self-functionalized CuTiNCs. Interestingly, a considerable and significant biocide performance was detected at 50 µg/mL of CuTiNCs against some human and plant pathogens, compared to monometallic counterparts. Further, CuTiNCs (200 µg/mL) ceased significantly the development of Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans biofilms by 80.3 ± 1.4, 68.7 ± 3.0 and 55.7 ± 3.0%, respectively. Whereas, 64.63 ± 3.5 and 89.82 ± 4.3% antimicrofouling potentiality was recorded for 100 and 200 µg/ml of CuTiNCs, respectively; highlighting their destructive effect against marine microfoulers cells and decaying of their extracellular polymeric skeleton as visualized by SEM. Moreover, CuTiNCs (100 and 200 µg/ml) exerted significantly outstanding disinfection potency within 2 h by reducing the microbial load (i.e., total plate count, mold & yeast, total coliforms and faecal Streptococcus) in domestic and agricultural effluents reached >50%. CONCLUSION: The synergistic efficiency provided by CuNPs and TiNPs in mycofunctionalized CuTiNCs boosted its recruitment as antiphytopathogenic, antibiofilm, antimicrofouling and disinfectant agent in various realms.

Association between a diagnosis of diabetes mellitus and smoking abstinence: An analysis of the National Health Interview Survey (2006-2018).

OBJECTIVE: Both diabetes and smoking significantly increase the risk of cardiovascular disease (CVD). Understanding whether a diagnosis of diabetes can be leveraged to promote smoking cessation is a gap in the literature. METHODS: We used data from the US National Health Interview Survey, 2006 to 2018, to investigate the relationship between self-report of diagnosis of diabetes and subsequent smoking abstinence among 142,884 respondents who reported regular smoking at baseline. Effect sizes were presented as hazard ratios (HRs) derived from multivariable Cox regression models adjusted for potential confounders using diabetes as a time-dependent covariate. Subgroup-specific estimates were obtained using interaction terms between diabetes and variables of interest. RESULTS: A self-reported diagnosis of diabetes was associated with smoking abstinence (HR: 1.21; 95% CI: 1.16 to 1.27). The strength of the association varied based on race (P for interaction: 0.004), where it was strongest in African Americans (HR: 1.44; 95% CI: 1.29 to 1.60); income (P for interaction <0.001), where it was strongest in those with a yearly income less than $35,000 (HR: 1.45; 95% CI: 1.36 to 1.53); and educational attainment (P for interaction <0.001), where it was strongest in those who did not attend college (HR: 1.48; 95% CI: 1.40 to 1.57). CONCLUSION: Among adults who smoke, a diagnosis of diabetes is significantly associated with subsequent smoking abstinence. The association is strongest in socially disadvantaged demographics, including African Americans, low-income individuals, and those who did not attend college.

Cardiac positron emission tomography and other modalities for coronary artery disease assessment: A snapshot from the medicare data.

BACKGROUND: Positron emission tomography (PET) is an important tool for assessing coronary artery disease (CAD), but its widespread utilization is limited due to various factors, including limited local champion availability. This study aims to compare the frequency of PET procedures and their interpreters with other common CAD assessment modalities. METHODS: Using Medicare data, we examined the number of cardiac PET procedures billed and compared them with single-photon emission computed tomography (SPECT), coronary computed tomography angiography (CCTA), stress magnetic resonance imaging (MRI), and stress echocardiography. Healthcare Common Procedure Coding System codes were used to identify procedures. We calculated the total number of PET myocardial perfusion imaging (MPI) procedures, the proportion of PET/CT and myocardial blood flow (MBF) assessments, and the median number of studies read per physician. We also analyzed the trends in the use of different CAD assessment modalities between 2018 and 2022. Descriptive statistics summarized the data. RESULTS: In 2022, Medicare billed for 212,106 PET MPI scans. SPECT was six times more frequent (1,343,519), whereas stress echocardiography (201,676) and CCTA (118,734) had similar or lower use. Stress MRI (3,932) was least used. Of the PET MPI scans, 46% were PET/CT, and 39% included MBF measurements. Cardiologists interpreted 86% of PET scans, with a median of 58 studies per reader; 23% interpreted ≤25 studies annually. SPECT had a median of 63 studies per reader, and CCTA, stress MRI, and stress echocardiography had medians of 27, 20, and 24, respectively. PET, CT, and MRI use increased from 2018 to 2022, whereas SPECT and stress echocardiography declined. CONCLUSION: In the Medicare population, radionuclide perfusion imaging (SPECT and PET) remained the preferred method for assessment of CAD, with SPECT being the most frequently used modality and PET being the second most frequently used modality for this application. However, PET/CT and MBF are underutilized, limiting diagnostic and prognostic capabilities. Efforts to enhance education and awareness of PET's advantages and to address barriers to its wider adoption are essential to maximize its clinical benefits and improve patient outcomes.

Insights into the current state of knowledge, practice, and attitudes of physicians regarding gastrointestinal motility disorders in Egypt.

BACKGROUND: Gastrointestinal (GI) motility disorders are common in clinical settings, but physicians still lack sufficient understanding and effective management of these conditions. METHODS: This research assessed Egyptian physicians' knowledge, practices, and attitudes towards GI motility disorders. A cross-sectional survey employing a self-administered questionnaire was carried out among physicians in Egypt. The questionnaire addressed various aspects of physicians' understanding, practices, and attitudes regarding GI motility disorders. Data analysis was conducted using descriptive statistics and presented as frequencies and percentages. RESULTS: A total of 462 physicians took part in the study. Although nearly two-thirds of them knew about GI motility studies, a notable proportion lacked adequate knowledge about GI motility disorders. Notably, 84.2% correctly identified dysphagia as a critical symptom suggestive of an upper GI motility disorder. However, 13.4% incorrectly linked hematemesis with an upper GI motility disorder, and 16.7% expressed uncertainty. In terms of practice, around half of the participants encountered a small number of patients with GI motility disorders (less than 5 per week or even fewer). Only 29.7% felt confident in managing patients with motility disorders. Most participating physicians expressed a willingness to participate in training programs focused on motility disorders. CONCLUSIONS: This study underscores a knowledge gap among Egyptian physicians concerning GI motility disorders. It suggests the necessity of tailored education and training programs to improve their competency and practice in this domain.

Prevalence and short-term clinical impacts of new-onset diabetes mellitus among patients with COVID-19 in jazan region, Saudi Arabia.

BACKGROUND: Diabetes Mellitus is a major predictor for severity and mortality that is increased by 50% in COVID-19 infection. The aim of this study is to estimate the prevalence of new-onset DM among patients with COVID-19 and examined the short clinical outcomes of the disease. METHOD: This is a retrospective study of revising electronic medical records to assess the prevalence of new-onset DM in COVID-19 patients and its impact on the severity of the disease. Adult patients with confirmed COVID-19 during the period from June 2020 to December 2021 were enrolled. RESULTS: 725 patients were included. 53.8% of them were males and 46.2 were females, the mean age was 43.35 ± 16.76. 13.2% were diabetics; 2.2% with preexisting DM and 11.0% had new-onset DM. 6.34% had coexisting medical conditions. DKA at presentation was observed in 6 patients (0.8%) of newly diagnosed DM. There is a significant correlation between age and family history (FH), and BMI and new-onset DM (P < 0.05). The overall mortality rate was 2.2%, and it was significantly higher in diabetics in comparison to non-diabetics (P < 0.001). 8.6% had persistent hyperglycemia after 4 months of follow-up. CONCLUSION: The prevalence of COVID-19 related new-onset DM was correlated significantly with disease severity and mortality rate. Age, FH, and BMI, were the major predictors. We recommend that frequent monitoring of blood glucose for patients with COVID-19 infections to detect DM, therefore, prompt treatment can be initiated.

Intravascular imaging-guided versus angiography-guided percutaneous coronary intervention: a systematic review and bayesian network meta-analysis of randomized controlled trials.

BACKGROUND: Percutaneous coronary intervention (PCI) has become one of the most commonly performed interventional life-saving procedures worldwide. Intravascular Imaging (intravascular ultrasound (IVUS) and optical coherence tomography (OCT)) have initially evolved to guide PCI compared with angiography. However, this technology is not universally employed in all PCI procedures, and there is ongoing controversy regarding its additional benefits to patient outcomes. We aim to estimate the efficacy and safety of imaging modalities during PCI, allowing pre-, per, and post-intervention assessment of coronary vascularization. METHODS: A systematic review and Bayesian network meta-analysis of randomized controlled trials (RCTs), which were retrieved from PubMed, WOS, SCOPUS, EMBASE, and CENTRAL through September 2023. We used R, version 4.2.0. Effect sizes will be presented as odds ratios with accompanying 95% credible intervals. PROSPERO ID: CRD42024507821. RESULTS: Our study, encompassing 36 RCTs with a total of 17,572 patients, revelead that compared to conventional angiography, IVUS significantly reduced the risk of major adverse cardiovascular events (MACE) (OR: 0.71 [95% CrI: 0.56 to 0.87]) but not OCT (OR: 0.91 [95% CrI: 0.62 to 1.39]), IVUS and OCT significantly reduced the risk of cardiac death (OR: 0.50 [95% CrI: 0.33 to 0.76]) and (OR: 0.55 [95% CrI: 0.31 to 0.98]), respectively, IVUS significantly reduced the risk of target vessel-related revascularization (OR: 0.60 [95% CrI: 0.48 to 0.75]) but not OCT (OR: 0.86 [95% CrI: 0.60 to 1.19]), IVUS and OCT significantly reduced the risk of stent thrombosis (OR: 0.50 [95% CrI: 0.28 to 0.92]) and (OR: 0.48 [95% CrI: 0.22 to 0.98]), respectively, IVUS significantly reduced the risk of re-stenosis (OR: 0.65 [95% CrI: 0.46 to 0.88]) but not OCT (OR: 0.55 [95% CrI: 0.15 to 1.99]), neither IVUS (OR: 0.97 [95% CrI: 0.71 to 1.38]) nor OCT (OR: 0.75 [95% CrI: 0.49 to 1.22]) were associated with statistically significant reductions in all-cause mortality, neither IVUS (OR: 0.70 [95% CrI: 0.45 to 1.32]) nor OCT (OR: 0.81 [95% CrI: 0.47 to 1.59]) were associated with statistically significant reductions in target vessel failure, neither IVUS (OR: 0.88 [95% CrI: 0.43 to 2.44]) nor OCT (OR: 0.81 [95% CrI: 0.37 to 2.04]) were associated with statistically significant reductions in target lesion failure, and neither IVUS (OR: 0.82 [95% CrI: 0.60 to 1.06]) nor OCT (OR: 0.84 [95% CrI: 0.59 to 1.19]) were associated with statistically significant reductions in myocardial infarction. CONCLUSION: Intravascular imaging-guided, including IVUS and OCT, improved the postinterventional outcomes of PCI, notably suggesting their advantage over traditional angiography with no significant difference between IVUS and OCT.

Ginger and its constituents in asthma: a mini-review.

OBJECTIVE: The primary objective of this review is to focus on research findings that aim to determine the immunomodulatory action of ginger's active components and the molecular mechanisms that reduce asthma. The study aims to provide an overview of the scientific literature available on ginger's efficacy in treating allergic asthma. DATA SOURCE: The mouse model of asthma has been used to investigate the actions of ginger and its active compounds on allergies and asthma. Various studies and scientific literature on ginger's health-improving qualities and its traditional use have been examined. RESULTS: The findings indicate that ginger and its active ingredients have anti-asthmatic features and a suppressive impact on mast cell production of histamine. Animals given ginger and compounds derived from ginger demonstrate a notable reduction in allergic response, suggesting a significant role in lowering the allergic reaction. CONCLUSION: While ginger shows promise as a potential treatment for allergies and asthma due to its anti-inflammatory, antibacterial, antidiabetic, anticancer, and antioxidant effects, further examination, extrapolation, and confirmation of these results are necessary before utilizing ginger and its active components in human treatments. This review highlights the need for additional research and provides an overview of the current scientific literature on ginger's efficacy in treating allergic asthma.

Discovery of novel thiazole derivatives containing pyrazole scaffold as PPAR-γ Agonists, α-Glucosidase, α-Amylase and COX-2 inhibitors; Design, synthesis and in silico study.

A novel series of thiazole derivatives with pyrazole scaffold 16a-l as hybrid rosiglitazone/celecoxib analogs was designed, synthesized and tested for its PPAR-γ activation, α-glucosidase, α-amylase and COX-2 inhibitory activities. Regarding the anti-diabetic activity, all compounds were assessed in vitro against PPAR-γ activation, α-glucosidase and α-amylase inhibition in addition to in vivo hypoglycemic activity (one day and 15 days studies). Compounds 16b, 16c, 16e and 16 k showed good PPAR-γ activation (activation % ≈ 72-79 %) compared to that of the reference drug rosiglitazone (74 %). In addition, the same derivatives 16b, 16c, 16e and 16 k showed the highest inhibitory activities against α-glucosidase (IC50 = 0.158, 0.314, 0.305, 0.128 µM, respectively) and against α-amylase (IC50 = 32.46, 23.21, 7.74, 35.85 µM, respectively) compared to the reference drug acarbose (IC50 = 0.161 and 31.46 µM for α-glucosidase and α-amylase, respectively). The most active derivatives 16b, 16c, 16e and 16 k also revealed good in vivo hypoglycemic effect comparable to that of rosiglitazone. In addition, compounds 16b and 16c had the best COX-2 selectivity index (S.I. = 18.7, 31.7, respectively) compared to celecoxib (S.I. = 10.3). In vivo anti-inflammatory activity of the target derivatives 16b, 16c, 16e and 16 k supported the results of in vitro screening as the derivatives 16b and 16c (ED50 = 8.2 and 24 mg/kg, respectively) were more potent than celecoxib (ED50 = 30 mg/kg). In silico docking, ADME, toxicity, and molecular dynamic studies were carried out to explain the interactions of the most active anti-diabetic and anti-inflammatory compounds 16b, 16c, 16e and 16 k with the target enzymes in addition to their physiochemical parameters.

New 2-oxoindole derivatives as multiple PDGFRα/ß and VEGFR-2 tyrosine kinase inhibitors.

Two new series of N-aryl acetamides 6a-o and benzyloxy benzylidenes 9a-p based 2-oxoindole derivatives were designed as potent antiproliferative multiple kinase inhibitors. The results of one-dose NCI antiproliferative screening for compounds 6a-o and 9a-p elucidated that the most promising antiproliferative scaffolds were 6f and 9f, which underwent five-dose testing. Notably, the amido congener 6f was the most potent derivative towards pancreatic ductal adenocarcinoma MDA-PATC53 and PL45 cell lines (IC50 = 1.73 µM and 2.40 µM, respectively), and the benzyloxy derivative 9f was the next potent one with IC50 values of 2.85 µM and 2.96 µM, respectively. Both compounds 6f and 9f demonstrated a favorable safety profile when tested against normal prostate epithelial cells (RWPE-1). Additionally, compound 6f displayed exceptional selectivity as a multiple kinase inhibitor, particularly targeting PDGFRα, PDGFRß, and VEGFR-2 kinases, with IC50 values of 7.41 nM, 6.18 nM, and 7.49 nM, respectively. In contrast, the reference compound Sunitinib exhibited IC50 values of 43.88 nM, 2.13 nM, and 78.46 nM against the same kinases. The derivative 9f followed closely, with IC50 values of 9.9 nM, 6.62 nM, and 22.21 nM for the respective kinases. Both 6f and 9f disrupt the G2/M cell cycle transition by upregulating p21 and reducing CDK1 and cyclin B1 mRNA levels. The interplay between targeted kinases and these cell cycle regulators underpins the G2/M cell cycle arrest induced by our compounds. Also, compounds 6f and 9f fundamentally resulted in entering MDA-PATC53 cells into the early stage of apoptosis with good percentages compared to the positive control Sunitinib. The in silico molecular-docking outcomes of scaffolds 6a-o and 9a-p in VEGFR-2, PDGFRα, and PDGFRß active sites depicted their ability to adopt essential binding interactions like the reference Sunitinib. Our designed analogs, specifically 6f and 9f, possess promising antiproliferative and kinase inhibitory properties, making them potential candidates for further therapeutic development.

Robotic-assisted versus laparoscopic-assisted extended mesorectal excision: a comprehensive meta-analysis and systematic review of perioperative and long-term outcomes.

BACKGROUND: Concurrent neoadjuvant chemo-radiation (nCRT) with total mesorectal excision (TME) alone sometimes fails to cure lateral lymph node metastasis (LLNM). Therefore, additional lateral lymph node dissection (LLND) can help in the treatment of these patients. This is what we refer to as extended total mesorectal excision (eTME). Such operations (TME alone or eTME) can be performed using conventional laparoscopic techniques and robotic-assisted techniques as well. Our meta-analysis aims to compare the results of robot-assisted (R-eTME) versus laparoscopic-assisted extended mesorectal excision (L-eTME) in terms of short- and long-term outcomes. METHODOLOGY: Databases searched using title and abstract included Medline (via PubMed), Web of Science, Scopus, and Embase, up to February 20, 2024. All studies that documented robotic versus laparoscopic procedures for extended total mesorectal excision (R-eTME versus L-eTME) and reported more than two relevant outcomes, were included in the study. RESULTS: Our meta-analysis demonstrates four significant outcomes (operative time, urinary complications, overall recurrence, and admission days) between the laparoscopic and robotic groups. The robotic approach shows advantages over the laparoscopic approach in these outcomes except for the operative time (minute), which was longer in the robotic group compared to the laparoscopic group. The laparoscopic group is associated with a higher overall recurrence than the robotic group with an Odds Ratio of 2(95% CI, 1-4, p = 0.05). CONCLUSION: This meta-analysis study showed that the R-eTME group had a lower recurrence rate compared to the L-eTME group. Additionally, hospital admission days increased significantly in the laparoscopic group. Other long-term outcomes did not differ significantly between the two groups. Short-term outcomes were similar, except for more urinary complications in the laparoscopic group. In conclusion, the study suggests that robotic surgery may offer advantages over laparoscopic surgery for eTME. Further research and analysis could provide further insight into the potential benefits of robotic surgery in this procedure, particularly when surgeon experience, center volume, and learning curve are taken into consideration.

Insight into hazards and control of transfusion-transmitted infections in Egypt: A narrative review.

Blood transfusion is a critical life-saving medical intervention, but it carries the risk of transfusion-transmitted infections (TTIs) that can lead to serious consequences. TTIs include viral, bacterial, parasitic, and prion infections, transmitted through asymptomatic donor blood, contamination of stored blood products, or transfusion-related immunosuppression. Recognized global agents posing challenges to blood safety include human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), Syphilis, etc. Emerging pathogens like SARS-CoV-2, hepatitis E, and others present additional risks. The residual risk of TTIs, representing the likelihood of infected donations passing screening tests, varies globally. High-income countries generally show lower prevalence rates than low-income countries. In Egypt, the estimated prevalence rates for HIV, HBV, HCV, and syphilis markers among the donors are 0.23 %, 0.76 %, 2.33 %, and 0.24 %, respectively. In Egypt, specific residual risk estimates are scarce, but prevalence rates for key infections highlight existing challenges. The World Health Organization promotes a global blood safety strategy, advocating for national blood systems, voluntary non-remunerated donors, and quality-assured testing. Despite these measures, the establishment of a haemovigilance system which is critical for monitoring and preventing adverse events, including TTIs, is reported as lacking in Egypt. This highlights the importance of comprehensive surveillance and safety measures in the blood donation process to ensure universal access to safe blood. Primary health care can play a pivotal role in preventing TTIs.

Effects of antioxidant vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) administration on gene expression, metabolic, antioxidants and immunological profiles during transition period in dromedary camels.

BACKGROUND: Nutrition has a primary role for optimum expression of genetic potential, and most of the farmers have limited resources of green fodder. Hence, a fat-soluble vitamin, especially vitamin A and E and trace elements remained most critical in the animal's ration and affects their productive and reproductive performance adversely. Animals cannot be able to produce these vitamins in their bodies; hence, an exogenous regular supply is needed to fulfil the physiological needs and to maintain high production performance. This study elucidated effects of antioxidant vitamins (A, D, E) and trace elements (Cu, Mn, Se, Zn) administration on gene expression, metabolic, antioxidants and immunological parameters in dromedary camels during transition period. RESULTS: At 0 day, there were no appreciable differences in the expression patterns of the metabolic (IGF-I, ACACA, SCD, FASN, LPL, and BTN1A1) genes between the control and treatment groups, despite lower levels. A substantial variation in the mRNA levels of SOD1, SOD3, PRDX2, PRDX3, PRDX4, PRDX6, and AhpC/TSA was observed between the control and treatment groups, according to the antioxidant markers. In comparison to the control group, the treatment group displayed a significant up-regulation at 0 and 21 days. The treatment and control groups exhibited substantial differences in the mRNA values of IL-1α, IL-1ß, IL-6, and TNFα, as indicated by immunological markers. In comparison to the control group, there was a noticeable down-regulation in the treatment group at 0 and + 21 days. But IL10 produced the opposite pattern. No significant difference was observed in glucose, cholesterol, triglyceride, HDL, total protein, NEFA, BHBA, cortisol and IGF-1 levels between control and treatment group. The activity of serum GPx, SOD and TAC was significantly affected by time and treatment x time in supplemented groups as compared with control group. IL-1, IL-1, IL-6, and TNF were noticeably greater in the control group and lower in the treatment group. Additionally, in all groups, the concentration of all pro-inflammatory cytokines peaked on the day of delivery and its lowest levels showed on day 21 following calving. The IL-10 level was at its peak 21 days prior to calving and was lowest on calving day. CONCLUSION: The results demonstrated a beneficial effect of antioxidant vitamins and trace elements on the metabolic, antioxidant and immunological markers in dromedary camels throughout their transition period.

Metabolic profile and gene expression pattern of cytokines and antioxidants markers during different physiological stages in Barki ewes.

BACKGROUND: In livestock, identifying the physiological and reproductive stages is valuable in guiding management decisions related to nutrition, veterinary procedures, and breeding programs. To achieve this goal, a cohort of Barki ewes in this research underwent observation across three pivotal physiological conditions: pre-pregnancy, late pregnancy, and early lactation. Blood samples were collected to investigate the changes in serum metabolic profile as well as gene expression pattern of cytokines and antioxidants markers during these stages. RESULTS: Our results showed that during late pregnancy, there was a significant (P < 0.05) increase in red blood cells (11.9 ± 0.5 1012/L), hemoglobin (10.8 ± 0.4 g/dl) and neutrophils count (7 ± 0.1 109/L) with significant decrease (P < 0.05) of total white blood cell count (9.1 ± 0.05 109/L). The packed cell volume (%) and monocyte count showed a significant (P < 0.05) decrease during both late pregnancy and early lactation stages. The serum concentrations of glucose, cholesterol, GSH, GPx, SOD and catalase displayed significant (P < 0.05) decrease during late pregnancy and early-lactation. Notably, during late pregnancy, there was a significant (P < 0.05) increase in the serum concentrations of albumin, globulin, urea, IGF-1, and malondialdehyde with significant decrease (P < 0.05) of total protein (4.9 ± 0.08 g/dl). Additionally, during early lactation, there was a significant (P < 0.05) increase in the serum levels of non-esterified fatty acids, triiodothyronine (T3), and thyroxin (T4). The gene expression profiles of cytokines (IL-4, IL-6, IL-8, and NFKB) were decreased in the ewes during late pregnancy compared to pre-pregnant and early lactation stages. In addition, the expression profile of antioxidant genes (SOD, CAT, GPX, and Nrf2) was significantly upsurged in the non-pregnant ewes compared to late pregnancy and early lactation ones. CONCLUSIONS: The results concluded that different physiological status significantly affects the blood metabolic profile and gene expression pattern in Barki sheep. Our findings can be helpful in monitoring animal health and applying in breeding programs of Barki sheep under harsh environmental conditions.